Method of alleviating withdrawal symptoms

ABSTRACT

The use of lofexidine and its pharmaceutically acceptable salts in alleviating the adverse symptoms of tobacco withdrawal is disclosed.

This is a division of application Ser. No. 467,553, filed Feb. 17, 1983,now abandoned.

BACKGROUND OF THE INVENTION

One of the major problems facing our society today is the widespread useof addicting drugs by a great many individuals. Among the drug abuseproblems in the United States, alcoholism is the most serious in termsof economic loss, loss in productivity and psychological damage toindividuals and families. An estimated ten million people in thiscountry are afflicted with serious drinking problems.

Second in importance is the dependence of an ever increasing segment ofour population upon narcotic drugs, particularly among the youngerpeople. In 1970 J. Ingersoll suggested that there are from 120,000 to180,000 heroin users in this country alone, i.e., a ratio of 1 in 1,100to 1 in 1,700 persons (Statement before the U.N. Commission on NarcoticDrugs, Sept. 28, 1970).

Again, the habit forming tendencies of tobacco are well known, as arethe symptoms of tobacco withdrawal. Moreover, it is now well documentedthat tobacco consumption, particularly in the form of cigarette smoking,is hazardous to one's health. Smoking has been implicated as a causativeagent in such conditions as emphysema, lung, mouth and throat cancer,the aggravation of hypertension, atherosclerosis and in coronary arterydisease. Of the millions of people in this country who voluntarilyattempt to give up smoking each year, the long term success rate atpresent is only 3%.

There appears to be no common denominator for the dependency of thesevarious drug substances. Drug dependency occurs in people of all ages,having diverse backgrounds and at every socio-economic level. The onegeneralization that can be made, however, is that following a period ofdrug dependency, most individuals seek to escape their drug dependencybut find it extremely difficult to do. This is true whether thedependency is one based on narcotic substances, other drugs, tobacco oralcohol. In the case of narcotics substances, and in particular opiates,withdrawal is virtually impossible absent controlled and carefullymonitored hospital treatment. Moreover, the severe withdrawal symptomsthat are endured, frequently have a deleterious effect upon thephysical, mental and emotional well-being of the individual. In the caseof alcoholism, multiple detoxifications during the course of anindividual's lifetime are the rule.

Inasmuch as opiates and other drugs have certain behavioral andbiochemical effects which appear to involve catecholamineneurotransmitter systems, investigators have tried to mimic thewithdrawal of these drugs by administering drugs which antagonize thesetransmitter systems. U.S. Pat. No. 3,923,987 illustrates one suchattempt using pharmaceutical compositions consisting of N-(furyl orthienylmethyl)-14-oxy-7,8-dihydronormorphinone or norcodeinone in aneffort to antagonize the effects of opiate dependency. Deoxycytidine, amorphine antagonist, is also stated to be useful for the treatment ofmorphine addition and toxification, see U.S. Pat. No. 3,873,698.

These approaches have not met with much success, however, and the usualtreatment for narcotic or opiate withdrawal involves maintenancetherapy. Maintenance therapy is a relatively new approach to narcoticaddiction, pioneered predominately by Dole and Co-workers (Arch. Int.Med. 118, 304 (1966); J. Am. Med. Assn., 206, 2708 (1968) and New. Engl.J. Med. 280, 1372 (1969), wherein a narcotic substitute is administeredin lieu of the drug substance. The narcotic substitute most frequentlyused in maintenance therapy is methadone, more particularly thehydrochloride salt of methadone.

Detoxification via methadone maintenance, however, is a slow anddifficult process with patients frequently experiencing abstinence andwithdrawal symptoms due to methadone itself. Moreover, methadonemaintenance is potentially subject to abuse when administeredintravenously so as to obtain potentiated narcotic effects.

Recent studies have shown that clonidine,2-(2,6-dichloroanilino)-2-imidazoline relieves certain symptoms ofopiate withdrawal, Washton et al., Lancet, pp. 1078-9 (1980) and Gold etal., J. Am. Med. Assn. 243, pp. 343-6 (1980). Additionally, clonidinehas been suggested as a useful aid in the treatment of alcoholwithdrawal, Bjorkqvist, Acta Psychiat. Scand. 52, pp. 256-63 (1975).However, due to oversedation and the potentially serious decrease inblood pressure in some patients, this method of detoxification requiresthe close supervision of an inpatient setting. Moreover, many patientsdevelop a tolerance to the sedative effect of clonidine after severaldays and require additional night time sedation to alleviate insomnia.

Thus, it can be seen that there exists an urgent need for a drug that isuseful in alleviating the effects of withdrawal from a wide variety ofaddicting drug substances, which drug is safe and non-addicting in andof itself, and which does not possess the serious disadvantages of someof the compounds used in the past for this purpose.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating drug dependentindividuals who wish to eliminate their drug dependency. Moreparticularly, this invention relates to the alleviation of the effectsof drug withdrawal by the administration of lofexidine to individualswho are dependent upon such drugs or drug substances as alcohol,tobacco, opium, heroin, barbiturates, benzodiazepines and methadone. Inaddition, this invention relates to the alleviation of drug-likewithdrawal symptoms wherein the adverse symptoms are those associatedwith pre-menstrual tension and peri-meanopausal flushing. A preferredembodiment of this invention is the use of lofexidine in alleviating theadverse symptoms of alcohol withdrawal in the treatment of alcoholism.

In accordance with the present invention it has been discovered thatwhen an individual or patient undergoes withdrawal from harmfuladdictive drugs, the withdrawal syndrome created by the completeabstinence of the addicting drug can be alleviated or materiallyminimized by the administration of an anti-withdrawal effective amount,or drug antagonistic effective amount, of lofexidine. By usinglefexidine in accordance with the teachings of this invention, some orall of the withdrawal symptoms that might normally be encountered arealleviated or eliminated.

Thus, the present invention provides a method of alleviating orminimizing the adverse symptoms of withdrawal from the aforementioneddrugs, thereby making it easier for a drug dependent individual to ridhimself of his drug dependency.

In addition, the rapid lowering of circulating hormone levels in womenexperiencing pre-menstrual syndrome, and in man or women experiencingmenopause, frequently results in adverse symptoms that are similar tothose which an individual or patient experiences while undergoingwithdrawal from addictive drugs. Accordingly, this invention alsoprovides a method of alleviating or easing the adverse symptomsassociated with pre-menstrual tension and peri-menopausal flushing.

DETAILED DESCRIPTION OF THE INVENTION

Whereas clonidine has been found to be useful in easing the pain anddiscomfort of opiate withdrawal in patients attempting to detoxify fromheroin or methadone addiction, the potent sedative and antihypertensiveeffects of this drug limits its usefulness.

Lofexidine, 2-[α(2,6-dichlorophenoxy)ethyl]-Δ² -imidazoline, is anexperimental compound which is related to clonidine. Like clonidine,lofexidine has been found to have antihypertensive activity in man,Burke et al. Clin. Pharmacol. Therap. 21, pp. 99-100 (1977).Additionally, lofexidine has recently been reported to block morphinewithdrawal signs in addicted rats, Pharmacol. Biochem. Behav. 12, pp.573-5 (1979).

I have now found that lofexidine is extremely effective in alleviatingor minimizing many of the symptoms associated with drug withdrawal. Inparticular, lofexidine is useful in alleviating the adverse symptomsmost frequently associated with alcohol and narcotic withdrawal.

The term drug or drug substance as used herein is intended to encompassthose addicting drugs or drug substances including alcohol, tobacco,opium, heroin, methadone, barbiturates such as phenobarbital,,secobarbital or pentobarbital, and benzodiazepines such aschloridiazepoxide or diazepam. In addition, for purposes of thisinvention, the term drug or drug substance is intended to include thosehormones or biochemical agents which are physiologically responsible forthe drug-like withdrawal symptoms associated with pre-menstrual tensionand peri-menopausal flushing.

The various withdrawal symptoms that are alleviated in accordance withthe teachings of this invention will, of course, vary depending upon theparticular type of addiction being treated. Moreover, these symptomswill also vary depending upon such factors as age, sex and extent anddegree of the individual's drug dependency.

In many cases of alcoholism and narcotic withdrawal, the patient firstbecomes functional a week or more following cessation of the addictingdrug. Accordingly, before any rehabilitation or proper medical treatmentcan occur, the physician must frequently wait a week or more post-drugwithdrawal until the patient has become stabilized. One of the principaladvantages of the present invention is the rapid onset of improvement inpatients undergoing withdrawal symptoms. Thus, in some instances,patients are practically asymptomatic after 48 hours of lofexidinetherapy, thereby enabling rehabilitation to occur earlier resulting in ashorter in-patient period.

Some of the adverse symptoms associated with drug withdrawal which arealleviated in the practice of this invention are: eating disturbances,vomiting, nausea, diarrhea, sweating, flushing, hypertension, insomnia,convulsions, tremors, lethargy, muscle/bone pains, cramps, tinnitus,anxiety, depression, tension, hallucinations, nightmares, delusions,fever, garbled speech, weakness, apprehension, heightened emotionaltone, confusion, tachycardia and, of course, an intense craving for theaddicting drug. For persons undergoing pre-menstrual tension orperi-menopausal flushing relates symptomology such as: dizziness,lightheadedness, irritability, nervousness, dry mouth, increased thirstor appetite, depression, headache, swelling, stiffness, oldema orsleepiness, is also alleviated in the practice of this invention.

The alleviation of these adverse symptoms of drug withdrawal can beconveniently established using out-patient drug-dependent volunteers.Inasmuch as many of these adverse symptoms above are subjective innature, the efficacy of lofexidine is determined on the basis of acomparison of various withdrawal symptom scales. In general, varioussymptoms are noted and numerical values ranging from 0 (none) to 10(severe) are assigned thereto by the patient and totaled. Total scoresare compared before, during and after withdrawal. Where possible thesescores are accompanied by physical and laboratory examinations includingblood pressure and electrocardiogram determinations under thesupervision of a physician.

In the case of narcotic withdrawal, subjects who report no illicitnarcotic use during the preceding 10 days receive a naloxone challengeon day 11. Naloxone is a narcotic antagonist which will precipitate awithdrawal reaction when given to individuals dependent upon narcotics.In subjects who reported that they have used an illicit narcotic, thenaloxone challenge is postponed until it poses a minimal risk ofprecipitating a withdrawal reaction in the patient. Subjects who passthe naloxone challenge are treated with naltrexone, a milder narcoticantagonist, and are then considered to be successfully detoxified.

In the case of tobacco withdrawal, outpatient data is considered to beunreliable. Thus, data is gathered from patients who are generallyhospitalized for medical reasons relating primarily to pulmonarydisease, and from patients who have a history of smoking at least 20cigarettes per day for one year or more, Lofexidine or placebo (in thecase of double-blind studies) are administered and physical signs, suchas blood and urine, are monitored. Additionally, self-evaluation scalesrelating to specific withdrawal symptoms including appetite, mood,attention span, sleep characteristics and craving for tobacco arerecorded daily. Abstinence from tobacco for a period of 3 months isgenerally considered a cure.

Lofexidine can be incorporated in any suitable manner with apharmaceutically acceptable carrier for administration to the patient.The compound can be orally administered in the form of a suspension,elixir, powder, capsule, tablet, lozenge and the like, or it may beadministered parenterally. The preferred mode of administration is oralvia a capsule, tablet or powder mix that can be dissolved in a liquid.

The pharmaceutical vehicle or carrier to be employed can include anyinert or excipient material normally employed in pharmaceuticalcompositions, such as, for example, binders, fillers, lubricants,stabilizers, preservatives, retardants, buffers, colors, etc. Examplesof such materials are cellulose derivatives such as, for example,microcrystalline cellulose, carboxymethyl cellulose, etc.; starches suchas, for example, potato, maize, wheat, arrowroot, amylopectine etc.;sugars such as, for example, lactose, sucrose, sacchrose and; otheringredients such as, for example, gelatine, calcium phosphate, stearicacid, talc, mannitol, sorbitol, calcium stearate, magnesium stearate,polyethylene glycols, agar, gum acacia, etc. Film coatings, entericcoatings and compositions wherein the active ingredient lofexidine hasbeen formulated as a sustained release preparation can also be favorablyemployed in the practice of this invention.

The dosage of an anti-withdrawal effective amount of lofexidine is thatamount of lofexidine which when administered to a drug dependentindividual will alleviate the adverse symptoms of withdrawal withoutadversely effecting the blood pressure of such an individual. Such ananti-withdrawal effective amount varies from individual to individualdepending upon the age, sex, weight, type, degree and length of drugdependency. Stating this another way, an anti-withdrawal effectiveamount is that amount of lofexidine which will antagonize the effects ofdrug withdrawal in a drug dependent individual.

Generally, this amount of lofexidine ranges from about 0.1 mg to about2.4 mg per day. In the treatment of methadone and narcotic withdrawal,the amount of lofexidine employed preferably rages from about 0.4 mg toabout 2.4 mg per day. In the treatment of alcohol withdrawal, the amountof lofexidine employed preferably ranges from about 0.4 mg to about 2.4mg per day. For use in the treatment of tobacco withdrawal, the amountof lofexidine employed preferably ranges from about 0.1 mg to 1.0 mg perday.

Lofexidine can be conveniently administered in tablet or capsule dosageunit forms. Preferably, lofexidine is administered daily in multipledosage unit forms containing 0.1 mg of lofexidine each. Even morepreferred in the practice of this invention is the administration of therequisite number of film coated tablets, containing 0.1 mg of lofexidineeach, administered three to four times daily.

Without further elaboration, it is believed that one skilled in the artcan practice the present invention to its fullest extent utilizing thepreceding description. The following examples are, therefore, merelyillustrative of the invention, and are not to be construed as limitingthe invention in any manner whatsoever.

EXAMPLE 1 Tablet Preparation

One thousand film coated tablets for oral use, each tablet containing0.1 mg or 0.2 mg of lofexidine, are prepared in accordance with thefollowing formulation:

    ______________________________________                                                         0.1 mg     0.2 mg                                            Core Tablet Ingredients                                                                        Tablet (gms)                                                                             Tablet (gms)                                      ______________________________________                                        Lofexidine hydrochloride                                                                       0.1        0.2                                               Lactose          138        137.9                                             Citric acid      18.5       18.5                                              Povidone         1.6        1.6                                               Microcrystalline cellulose                                                                     8.5        8.5                                               Calcium stearate 2.1        2.1                                               Sodium lauryl sulfate                                                                          1.1        1.1                                               Purified Water   q.s.       q.s.                                              ______________________________________                                        Film Coating Ingredients                                                                              Grams                                                 ______________________________________                                        Opaspray ® K-1-2228, mixture of                                                                    1.8                                                  dyes, TiO.sub.2 and hydroxypropyl cellulose                                   Hydroxypropyl methylcellulose                                                                          1.8                                                  Methylene chloride      60.0                                                  3A Alcohol              13.5                                                  ______________________________________                                    

Citric acid is milled and the milled powder added to the lactose in asuitable mixer. Lofexidine and povidone are dissolved in approximately10 ml of water and used to granulate the citric acid-lactose mixture.The granulation so prepared is wet screened and the granules dried andground. Calcium stearate, sodium lauryl sulfate and microcrystallinecellulose are added, mixed and the resulting mixture compressed intotablets.

The coating suspension is prepared by dissolving hydroxypropylmethylcellulose in methylene chloride. The alcohol and Opaspray areadded and the suspension homogenized. Core tablets are warmed in abaffled rotating coating pan and the coating applied via intermittentspraying and drying until a suitable tablet coat is obtained.

EXAMPLE 2 Capsule Preparation

One thousand two piece hard gelatin capsules for oral use are preparedas follows:

    ______________________________________                                        Ingredients         Grams                                                     ______________________________________                                        Lofexidine hydrochloride                                                                          0.1                                                       Lactose             197.9                                                     Magnesium stearate  2.0                                                       ______________________________________                                    

The above formulation is prepared by passing each of the dry powdersthrough a fine mesh screen. The lofexidine hydrochloride is thoroughlydistributed in the lactose and the magnesium stearate added. All of thepowders are well mixed and filled via conventional techniques into No. 4two-piece hard gelatin capsules having a net fill of 200 mg each. Eachcapsule so prepared contains 0.1 mg of lofexidine hydrochloride.

EXAMPLE 3 Powder Mix For Oral Solution

    ______________________________________                                        Ingredients         Grams                                                     ______________________________________                                        Lofexidine hydrochloride                                                                          .01                                                       Lactose             199.9                                                     ______________________________________                                    

The above formulation is prepared by passing each of the dried powdersthrough a fine screen and the lofexidine hydrochloride is thoroughlydistributed in the lactose. One teaspoon of the above powder whendissolved in water or juice is equivalent to a dosage of approximately0.2 mg of lofexidine hydrochloride.

EXAMPLE 4 Alcohol Withdrawal

Eleven alcohol dependent patients who have expressed a desire to bedetoxified and who are not currently using tricyclic antidepressant, MAOinhibitor or neuroleptic drugs are given an initial morning dose of 0.2mg of lofexidine. This is followed in about two hours by a 0.1 mg doseof lofexidine, if necessary. The next dose is administered approximately8 hours after the first dose and ranges from 0.2-0.4 mg of lofexidinedepending upon the patient's response to earlier doses. The final doseof the day is administered approximately 16 hours after the first doseand ranges from 0.2-0.5 mg of lofexidine depending upon the patient'sresponse to earlier doses.

The second and final day of dosing comprises three doses of from 0.2 to0.5 mg of lofexidine, depending upon the optimum dose on day 1,administered approximately 8 hours apart.

The following observations are taken and evaluated immediately prior tothe first dosage, six and twelve hours after the first dosage, and thenonce each day for the duration of the study: Brief Psychiatric RatingScale (BPRS), Overall and Gorham, Psychol. Rep., 10:799-812, 1962, theFabre-McLendon Alcohol Withdrawal Symptom Scale (FMS), theMcLendon-Fabre Self-Rating Alcohol Withdrawal scale (MFS), and theAlcohol Withdrawal Symptom Scale (AWSS). The various symptoms observedare numerically rated on the basis of pre-determined values, in whichthe symptoms are rated according to their presence or absence, and ifpresent in accordance with their intensity. The mean scores for alleleven patients treated with lofexidine are as follows:

    ______________________________________                                                     Pre-Drug Score                                                                            48 Hour Score                                        Rating Score Mean + S.D. Mean + S.D.                                          ______________________________________                                        MFS          30.6 ± 8.7                                                                             13.2 + 7.8*                                          FMS          13.2 ± 1.1                                                                               5 ± 2.4*                                        AWSS         24.7 ± 5.7                                                                             11.1 ± 6.2*                                       BPRS         13.7 ± 1.2                                                                              9.4 ± 2.0*                                       ______________________________________                                         *Value is significantly (P 0.05) different from the corresponding predrug     value.                                                                   

Comparison of the mean pre-drug scores with those scores obtainedfollowing 48 hours of treatment with lofexidine demonstrate a markeddecrease in withdrawal symptoms for all four rating scales which isstatistically significant. Moreover, the patients are relativelyasymptomatic after only 48 hours of lofexidine therapy, whereas othermodalities of treatment generally require 7 days to achieve this degreeof symptomatic relief.

EXAMPLE 5 Methadone Withdrawal

Fifteen methadone-dependent (10-25 mg/day) outpatients who who haveexhibit no serious medical or psychiatric illness and who have expresseda desire to undergo detoxification are given the following regimen.

On day 1 the patients receive their usual methadone dose and begin aself-administered regimen of 0.1 to 0.4 mg of lofexidine. On day 2,methadone is abruptly discontinued by the substitution of placebo.During the course of this study, the dosage of lofexidine is increasedas necessary for individual patients, in accordance with the symptomsobserved, up to a maximum of 1.6 mg/day. Blood pressure, withdrawalsymptoms, and lofexidine effects are assessed daily. Subjective ratingsof lofexidine effectiveness in alleviating various pharmacologicaleffects are recorded on a scale ranging from zero (no withdrawalsuppression) to ten (complete suppresion).

Those subjects who report no illicit opiate usage during the preceding10 days are given a naloxone challenge on day 11 (2.0 mg I.V.) toconfirm opiate free status. Naloxone when given to narcotic dependentindividuals precipitates a withdrawal reaction. Subjects who report thatthey have used illicit opiates during the first 10 days post-methadonetreatment are permitted to continue on lofexidine. Additionally, thenaloxone challenge is postponed in those patients to a time at which itposes a minimal risk of precipitating a withdrawal reaction. Subjectswho pass the naloxone challenge are started on naltrexone, a mildnarcotic antagonist. Patients who receive naltrexone at days 11-21 areconsidered successful detoxifications, whereas patients who return toopiate or methadone use and fail to begin naltrexone are consideredunsuccessful detoxifications. The results are summarized as follows.

    __________________________________________________________________________                    Highest       Patient's                                       Patient                                                                           Methadone                                                                           Days On                                                                             Lofexidine                                                                          Mean Effective-                                                                       Subjective                                                                          Physician's                                                                         Treatment                           No. Level (mg)                                                                          Lofexidine                                                                          Dose (mg)                                                                           ness Rating.sup.a                                                                     Evaluation.sup.b                                                                    Evaluation.sup.c                                                                    Outcome.sup.d                       __________________________________________________________________________    1   20    21    1.6   5.25    Much  Moderate                                                                            Success                             2   20    12    0.9   4.9     No info.                                                                            Moderate                                                                            Success                             3   20    10    0.6   6.6     Very much                                                                           Moderate                                                                            Success                             4   20    4     0.6   7.0     Much  Moderate                                                                            Dropout                             5   10    7     0.6   8.8     Very much                                                                           Marked                                                                              Dropout                             6   10    3     0.8   7.0     A little                                                                            Minimal                                                                             Dropout                             7   20    10    1.2   8.9     Very much                                                                           Marked                                                                              Success                             8   10    10    1.6   8.1     Very much                                                                           Marked                                                                              Success                             9   10    11    1.6   8.9     Very much                                                                           Marked                                                                              Success                             10  20    19    1.4   8.7     Very much                                                                           Marked                                                                              Success                             11  20    4     1.4   3.1     Moderately                                                                          Moderate                                                                            Dropout                             12  10    12    1.5   8.9     Very much                                                                           Marked                                                                              Success                             13  25    19    1.5   8.8     Moderately                                                                          Minimal                                                                             Failure                             14  20    15    1.5   8.0     No info.                                                                            No Info.                                                                            Dropout                             15  20    11    1.3   8.5     Very much                                                                           Marked                                                                              Success                             __________________________________________________________________________     .sup.a Difference in ratings of lofexidine's effectiveness in alleviating     various pharmacological effects between day 2 and last day of treatment (      no suppression; 10  complete suppression).                                   .sup.b Patient's feeling on "how the drug helped" at final examination.       .sup.c Physician's evaluation of therapeutic effect of the drug at final      examination.                                                                  .sup.d Clinical success is determined by a negative naloxone test.       

I claim:
 1. A method of alleviating the adverse symptoms associated withtobacco withdrawal which comprises the administration of ananti-withdrawal effective amount of lofexidine, or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.
 2. A methodaccording to claim 1 wherein the anti-withdrawal effective amount isfrom 0.1 to 1.6 milligrams of lofexidine per day.